title: Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target.
abstract: A handful of tumor-derived cell lines form the mainstay of cancer therapeutic development, yielding drugs with an impact typically measured as months to disease progression. To develop more effective breast cancer therapeutics and more readily understand their clinical impact, we constructed a functional metabolic portrait of 46 independently derived breast cell lines. Our analysis of glutamine uptake and dependence identified a subset of triple-negative samples that are glutamine auxotrophs. Ambient glutamine indirectly supports environmental cystine acquisition via the xCT antiporter, which is expressed on one-third of triple-negative tumors in vivo. xCT inhibition with the clinically approved anti-inflammatory sulfasalazine decreases tumor growth, revealing a therapeutic target in breast tumors of poorest prognosis and a lead compound for rapid, effective drug development.
authors.affiliation: UCSF/Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94115, USA. Electronic address: timmerma@cc.ucsf.edu.
authors.forename: Luika A
authors.initials: LA
authors.lastname: Timmerman
authors.forename: Thomas
authors.initials: T
authors.lastname: Holton
authors.forename: Mariia
authors.initials: M
authors.lastname: Yuneva
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Louie
authors.forename: Mercè
authors.initials: M
authors.lastname: Padró
authors.forename: Anneleen
authors.initials: A
authors.lastname: Daemen
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Denise A
authors.initials: DA
authors.lastname: Chan
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Ethier
authors.forename: Laura J
authors.initials: LJ
authors.lastname: van 't Veer
authors.forename: Kornelia
authors.initials: K
authors.lastname: Polyak
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005973:Glutamine / Q000378:metabolism / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D011379:Prognosis; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*
chemical_list: D027182:Amino Acid Transport System y+; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; C492255:Slc7a11 protein, mouse; D005973:Glutamine; D005978:Glutathione